One of the most dramatic symptoms associated with Alzheimer's disease (AD) and, to a lesser extent, with aging, is a gradual impairment in learning and memory. This impairment is in part due to the presence of plaques and tangles in several brain structures, including the cerebral cortex and the hippocampus, as well as to the degeneration of selectively vulnerable neuronal populations. Although the mechanisms involved in the neuropathologies associated with aging and AD are not known, it is widely accepted that alterations in glutamatergic transmission might play critical roles in both learning impairment and neuronal death. This view has been supported by numerous studies indicating the participation of glutamate receptors in both learning and memory and in neuronal degeneration. Our previous work has revealed the existence of several mechanisms regulating the properties of flutamate receptors and has documented the roe of these mechanisms in learning and memory and in neuronal degeneration in adult rat brain. The proposed studies are intended to expand these studies to the aging rat brain and to brain from AD patients and to test several hypotheses relating changes in glutamate receptors and /or in mechanisms regulating their characteristics to changes in synaptic plasticity and excitotoxicity in aged rats. Possible alterations in glutamate receptor properties and regulation in AD brain will also be evaluated. The following specific aims will be pursued: (1) to determine the changes in glutamate receptor properties and regulation in aging rat brain and human AD, (2) to study potential changes in mechanisms regulating glutamatergic transmission in aging rat brain and human AD, (3) to evaluate potential changes in the mechanisms linking glutamate receptors and neuronal degeneration in aging rat brain, and (4) in view of the regulation of the NMDA receptor by polyamines, to study potential correlation between CSF and blood polyamine levels and disease severity in AD patients. The research will use a variety of molecular and biochemical techniques to study the properties in young and old rats as well as in brain samples from AD patients. It will also use in vitro and in vivo models of synaptic plasticity to study mechanisms regulating glutamate receptors, glutamatergic transmission, and the excitotoxic properties of glutamate in young and old rats. These studies will provide important information concerning the mechanisms involved in age-related modifications of glutamatergic transmission and identify critical steps that could account for the learning deficits and neuronal damage observed with aging and AD. They might therefore suggest new avenues for designing optimal strategies to alleviate the learning deficits and to prevent the neuronal damage associated with these states.